Persistent Infection with <i>Pseudomonas aeruginosa</i> in Ventilator-associated Pneumonia

Solh, Ali A. El; Akinnusi, Morohunfolu E.; Wiener-Kronish, Jeanine P.; Lynch, Susan V.; Pineda, Lilibeth A.; Szarpa, Kristie R.

doi:10.1164/rccm.200802-239oc

Cited by 109 publications

(94 citation statements)

References 52 publications

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“…ExoS and ExoU are present as variable traits, which are mutually exclusive, with the ExoS genotype being more prevalent than ExoU [3]. The impact of the two toxins on the pathogen virulence is distinct because various studies suggest that ExoU-producing strains are associated with poor outcomes and high mortality rates [4].…”

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confidence: 99%

Molecular Detection of the VirulentExoUGenotype ofPseudomonas aeruginosaIsolated from Infected Surgical Incisions

Hassuna

2016

Surgical Infections

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Background: Pseudomonas aeruginosa is one of the major pathogens responsible for hospital-acquired infections, which harbor a wide array of virulence factors. The main aim of this study was to determine the frequency of the virulent ExoU genotype in relation to the ExoS genotype among isolated P. aeruginosa from infected surgical incisions, followed by phylogenetic analysis. Methods: A total of 66 P. aeruginosa isolates were identified by cultural and biochemical characteristics. All isolates were tested for antimicrobial susceptibility against the following antimicrobial agents: imipenem, amikacin, gentamicin, amoxycillin, cefotaxime, cefepime, and levofloxacin. Molecular detection of the ExoS and ExoU as well as two other virulence genes was done by polymerase chain reaction (PCR). Sequencing of ExoU gene and phylogenetic analysis was performed.Results: Approximately 81% of the isolated P. aeruginosa were multi-drug resistant. The ExoS genotype was more prevalent (63%) among the isolates than the ExoU genotype (18%), with 9% of the isolates possessing both toxins. LasB and AprA were detected in 63.6% and 27.2% of the isolates, respectively. An association was observed between the number of virulence genes and the presence of multi-drug resistance. All the ExoU were multi-drug resistant (MDR), whereas 71% of the ExoS were MDR. Phylogenetic analysis of ExoU gene showed a 99% similarity with four different strains. Conclusion: Despite the greater frequency of the ExoS genotype, the presence of the virulent MDR ExoU genotype isolates from surgical site infections is an alarming sign requiring further intervention and investigations.

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Molecular Detection of the VirulentExoUGenotype ofPseudomonas aeruginosaIsolated from Infected Surgical Incisions

Hassuna

2016

Surgical Infections

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“…This macromolecular delivery system for the intracellular injection of bacterial toxins and effector molecules has been under intense scrutiny as a target for vaccines and antibodies (11)(12)(13). Investigations of P. aeruginosa T3SS gene expression in human disease isolates reveal a correlation between exotoxin expression/ transport and increased disease severity and poor clinical outcomes (14)(15)(16)(17). The P. aeruginosa T3SS is a well-validated target for intervention in infections caused by this opportunistic pathogen.…”

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confidence: 99%

A Novel Anti-PcrV Antibody Providing Enhanced Protection against Pseudomonas aeruginosa in Multiple Animal Infection Models

Warrener¹,

Varkey²,

Bonnell³

et al. 2014

Antimicrob Agents Chemother

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Pseudomonas aeruginosa is a major cause of hospital-acquired infections, particularly in mechanically ventilated patients, and it is the leading cause of death in cystic fibrosis patients. A key virulence factor associated with disease severity is the P. aeruginosa type III secretion system (T3SS), which injects bacterial toxins directly into the cytoplasm of host cells. The PcrV protein, located at the tip of the T3SS injectisome complex, is required for T3SS function and is a well-validated target in animal models of immunoprophylactic strategies targeting P. aeruginosa. In an effort to identify a highly potent and protective monoclonal antibody (MAb) that inhibits the T3SS, we generated and characterized a panel of novel anti-PcrV MAbs. Interestingly, some MAbs exhibiting potent inhibition of T3SS in vitro failed to provide protection in a mouse model of P. aeruginosa infection, suggesting that effective in vivo inhibition of T3SS with anti-PcrV MAbs is epitope dependent. V2L2MD, while not the most potent MAb as assessed by in vitro cytotoxicity inhibition assays, provided strong prophylactic protection in several murine infection models and a postinfection therapeutic model. V2L2MD mediated significantly (P < 0.0001) better in vivo protection than that provided by a comparator antibody, MAb166, a well-characterized anti-PcrV MAb and the progenitor of a clinical candidate, KB001-A. The results described here support further development of a V2L2MD-containing immunotherapeutic and may suggest even greater potential than was previously recognized for the prevention and treatment of P. aeruginosa infections in high-risk populations.

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“…Morbidity and mortality associated with P. aeruginosa infections remain high despite the availability of antibiotics to which the bacterium is sensitive, and antibiotic resistance is an increasingly common problem in nosocomial infections (6).…”

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An Engineered Human Antibody Fab Fragment Specific for Pseudomonas aeruginosa PcrV Antigen Has Potent Antibacterial Activity

et al. 2009

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Pseudomonas aeruginosa is an opportunistic pathogen that can cause acute lung injury and mortality through the delivery of exotoxins by the type III secretion system (TTSS). PcrV is an important structural protein of the TTSS. An engineered human antibody Fab fragment that binds to the P. aeruginosa PcrV protein with high affinity has been identified and has potent in vitro neutralization activity against the TTSS. The instillation of a single dose of Fab into the lungs of mice provided protection against lethal pulmonary challenge of P. aeruginosa and led to a substantial reduction of viable bacterial counts in the lungs. These results demonstrate that blocking of the TTSS by a Fab lacking antibody Fc-mediated effector functions can be sufficient for the effective clearance of pulmonary P. aeruginosa infection.

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Persistent Infection with Pseudomonas aeruginosa in Ventilator-associated Pneumonia

Abstract: The increased apoptosis in neutrophils by the TTSS(+) isolates may explain the delay in eradication of Pseudomonas strains in patients with VAP. Short-course antimicrobial therapy may not be adequate in clearing the infection with a TTSS secretory phenotype.

Cited by 109 publications

References 52 publications

Molecular Detection of the VirulentExoUGenotype ofPseudomonas aeruginosaIsolated from Infected Surgical Incisions

Molecular Detection of the VirulentExoUGenotype ofPseudomonas aeruginosaIsolated from Infected Surgical Incisions

A Novel Anti-PcrV Antibody Providing Enhanced Protection against Pseudomonas aeruginosa in Multiple Animal Infection Models

An Engineered Human Antibody Fab Fragment Specific for Pseudomonas aeruginosa PcrV Antigen Has Potent Antibacterial Activity

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